He was the president of RENFE (the Spanish national railroad network) between 1967 and 1968. Calvo-Sotelo was elected solicitor (Deputy) of Franco's Cortes, representing industrialists in the Union of Chemical Industries, in 1971.[2] A monarchist, Sotelo was one of the founders of an association of politicians, mostly of Rightists and Center Rightists, which disguised as the Fedisa publishing firm helped Spain's peaceful transition into democracy.[2]

Calvo-Sotelo was designated Minister of Commerce by Carlos Arias Navarro to be in the first government of the Monarchy (December 1975 – July 1976).[2] He advocated total destruction of Franco's ideals instead of mere superficial changes that politicians like Navarro planned.[2] Calvo-Sotelo was kept in the cabinet of Adolfo Suárez upon his succession to premiership in 1976 and directed several centre-right and centre-left political associations into one party, the Union of the Democratic Centre (UCD).[2] The UCD won in both the June 1977 and the March 1979 elections[2] and Calvo-Sotelo was elected MP for Madrid.

Suárez decided to keep him in the Cabinet, first from 1978 to 1980 as Minister for Relations of the European Economic Community, then as Second Vicepresident in charge of economic affairs.[2] After the resignation of Suárez on 29 January 1981, he was supposed to be appointed Prime Minister (Presidente del Gobierno) on 23 February, and advocated Spain's proposed entry into NATO as soon as possible.[2] However, on that date a session of the Congress of Deputies was interrupted by the attempted coup of 23-F.[2] After the failed coup, his appointment as Prime Minister was confirmed on 25 February by the vote of all the UCD members of the congress and 21 others as well, giving him a majority of 186 to 158.[2] Splits in the UCD group led to the formation of three rival parties, the Democratic Action Party (Partido de Acción Democrática/PAD), which soon merged with the Spanish Socialist Workers' Party (PSOE), the Democratic and Social Centre (CDS) and Democratic Popular Party (PDP), resulting in the UCD being unable to count on sufficient support in the legislature. Fresh elections were called, resulting in a heavy defeat for the UCD, which won only 12 seats at the 1982 election compared to 168 in 1979. He served as Prime Minister until 1 December 1982 and was succeeded by the socialist Felipe González.[2]